PROCESS FOR PREPARING 2,4-DIHYDRO-6-PHENYL-1H-S-TRIAZOLO{8 4,3-a{9 {8 1,4{9 BENZODIAZEPIN-1-ONE COMPOUNDS

ABSTRACT

A process for the production of 2,4-dihydro-6-phenyl-1H-striazolo(4,3-a)(1,4)benzodiazepin-1-ones by treating a 1-halo-6phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine of the formula WHEREIN X is chlorine or bromine; wherein the A ring is substituted in position 8 with hydrogen, chlorine, or bromine and wherein the B ring is substituted in one or both ortho positions with hydrogen, chlorine, or fluorine, with phosphoric acid in high concentration.

[titted Patent [191 Hester, Jr.

[451 net. 254, 1974 PROCESS FOR PREPARING 2,4-D1HYDRO-6-PHENYL-lH-S-TRIAZOLO[4,3-a] [1 ,4]BENZOD IAZEPIN- ll-ONE COMPOUNDS [75] Inventor:Jackson B. Hester, Jr., Gelesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Sept. 17, 1973 [21] Appl. No.: 397,966

[52] US. lCl. 260/308 C, 260/239.3 D, 424/269 [51] Int. Cl C07d 57/02[58] Field of Search 260/308 C [56] References Cited OTHER PUBLICATIONSYork, 1961), p.453, QD4OOE4.

Primary Examiner-Alton D. Rollins [57] ABSTRACT A process for theproduction of 2,4-dihydro-6-phcny1-1H-s-triazolo[4,3-a][1,4]benzodiazepin-l-oncs by treating a1-halo-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine of the formulafluorine, with phosphoric acid in high concentration.

4 Claims, N0 Drawings l PROCESS FOR PREPARING2,4-DllHYlDRO-6-PHENYL-IH-S-TRIAZOLO[4,3- a] [l ,4IBENZODIAZEPlN-l-ONECOMPOUNDS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION II whereinX is chlorine or bromine; wherein the A ring is substituted in position8 with hydrogen, chlori'ne,.or bromine and wherein the B ring issubstituted in the ortho positions with hydrogen, chlorine, or fluorine.Compound 11 can be further alkylated, in position 2, by conventionalmethods as shown in U.S. Pat. Nos. 3,646,055 and 3,708,592. Theresulting products have the formula III wherein R is alkyl of l to 3carbon atoms, inclusive, and the A and B rings are defined as above.

The alkyl group therefore can be methyl, ethyl, propyl, and isopropyl.The most important substituents in formulae II and III are chlorine inthe 8 and orthoposition.

In carrying out the novel process a selected l-bromo or1-chloro-6-phenyl-4H-s-triazolo[4,3-

a][l,4]benzodiazepine 1, with the l-bromo species preferred, is heatedin excess of an aqueous mineral acid in the absence of any solvents.Hydrochloric acid, dilute sulfuric acid, andphosphoric acid, serve thispurpose, with phosphoric acid being preferred. The heating is carriedoutat -a temperature between l00l50 C. for a period of l to 10 hours. Afterthis time the product II is isolated by conventional procedures, usuallyby extraction, after neutralization with an aqueous base e.g., aqueoussodium or potassium hydroxide or carbonate. The extraction is carriedout with.

water-immiscible solvents such as benzene, ethyl acetate, methylenechloride, chloroform, Skellysolve B hexanes, mixtures thereof and thelike. After evaporation of the solvent the crude product is purified byconventionalprocedures e. g., crystallization, chromatography and thelike.

The starting compounds of formula I of this reaction and the methodof'preparation is described in detail in U.S. Pat. No. 3,573,324 and inPreparations I through The final compounds (II) of this reaction e.g,2,4- dihydro-6-phenyl-s-triazolo[4,3-a][1,4]benzodiazepinl-ones, havesedative, tranquilizing and anxiolytic effects. For example sedativeeffects for 8-chloro-2,4- dihydro-6-phenyll H-s-triazolo[4,3-a][1,4]benzodiazepin-l-one are shown by the following tests in mice: I

Chimney test: Med. Exp. 4, (1961)]: The effective intraperitoneal dosagefor 50% of mice (ED is 3.5 mg./kg. The test determines the ability ofmice to back up and out of a vertical glass cylinder within 30 seconds.At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. ED equals the dost of test compound at which 50% of themice remain in the dish, The Ed (intraperitoneal administration) in thistest is l mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than one minute.The ED (intraperitoneal administration) is 3.5 mg/kg.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound. Thirty minutes later the mice including control(untreated) mice are injected with nicotine salicylate (2 mg./kg.).. The

control mice show overstimulation, i.e., (l) running convulsionsfollowed by (2) topic extensor fits, followed by (3) death. Anintraperitoneal dosage of 1.6 mg jkg. of the test compound protected 50%of the mice against (3). The compounds of formula II can be used fortranquilization of mammals in pharmaceutical formulations and dosageforms as described in detail in U.S. Pat.

PREPARATION 1 l,8-Dichloro-6-phenyl-4H-s-triazolo[4,3 -a][1,4]-benzodiazepine.

A stirred mixture of 8-chloro-6-phenyl-4I-I-striazolo[4,3-a][1,4]benzodiazepine (2.95 g., 0.01mole), N-chloro-succinimide (1.48 g., 0.011 mole) and carbontetrachloride (200 ml.) was refluxed under a nitrogen atmosphere for 7hours and kept at ambient temperature for 16 hours. Water and enoughchloroform to dissolve the precipitated produce were added to themixture and the layers were separated. The aqueous layer was extractedwith chlorofrom and the combined organic solution was dried overanhydrous potas- PREPARATION 21-Bromo-8-chloro-6-phenyl-4H-s-triazolo-[4,3- a][1,4]benzodiazepine Astirred mixture of 8-ch1oro-6-phenyl-4l I-s-trizolo-[4,3-a][1,4]benzodiazepine (14.7 g., 0.05 mole), N- bromosuccinimide(8.9 g., 0.05 mole), and carbon tetrachloride (1 liter) was refluxed,under a nitrogen atmosphere for 4 hours, cooled and concentrated invacuo. The residue was mixed with water and extracted with chloroform.The extract was dried over anhydrous potassium carbonate andconcentrated. Crystallization of the residue from ethyl acetate gave7.74 g. of 1- bromo-8-chloro-6-phenyl-4H-s-triazolo[4,3-

a] l ,4]benzodiazepine of melting point 202.5206 C. The mother liquorwas concentrated and chromatographed on silica gel (500 g.) with 2.5%methanol- 97.5% chloroform. The product obtained from the column wasrecrystallized from ethyl acetate to give 3.01 g. of1-bromo-8-chloro-6-pheny1-4I-I-s-triazolo[4,3- a][l,4]benzodiazepine ofmelting point 205207. The analytical sample had a melting point of202-203.5 C.

Anal. calcd. for C l-l' BrClN C, 51.43; H, 2.70; Br, 21.39; Cl, 9.49; N,15.00. Found:

C, 51.32; H, 2.98; Br, 21.14; Cl, 9.59; N, 15.20.

PREPARATION 3 1,8-Dibromo-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine EXAMPLE 18-Ch1oro-2,4-dihydro-6-pheny1-1H-s-triazo1o[4,3-a]-1,4]benzodiazepin-l-one To 30 ml. of phosphoric acid, at roomtemperature, in a nitrogen atmosphere is added 1 g. (0.00268 mole) ofl-bromo-8-chloro-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine. Thismixture is heated to l 18-12l C. and kept at this temperature for 5hours. The mixture is then cooled and poured into about 500 ml. of iceand water. To this cold aqueous reaction mixture is added a sufficientamount of 50% aqueous sodium hydroxide to make it alkaline. The alkalinemixture is then extracted four times with ml. portions or chloroform;the chloroform extracts are combined, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The resulting residue iscrystallized from methylene chloride-ethanol to give 0.671 g. of8-chloro-2,4-dihydro-6-phenyl-lI-I-s-triazolo-[4,3-a][1,4]benzodiazepin-1-one of melting point 255.5257.5.

EXAMPLE 2 8-Chloro-2,4-dihydro-6-(o-chlorophenyl)-1 H-striazolo[4,3-a][1,4]benzodiazepin-1-one In the manner given in Example 1,1,8-dichloro-6-(o- I chlorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine was heated to C. with 60% aqueous sulfuric acidfor 6 hours to give 8-chloro-2,4-dihydro-6-(o-chlorophenyl)-1H-s-triazolo[4,3-a][1,4]benzodiazepin-l-one.

EXAMPLE 38-Chloro-2,4-dihydro-6-(o-fluorophenyl)-1l-I-striaz0lo[4,3-a][1,4]benzodiazepinl-one EXAMPLE 4 8-Chloro-2,4-dihydro-6-pheny1-1H-s-triazolo-[4,3-

a][1,4]benzodiazepin-l-one In the manner given in Example 1,1,8-dichloro-6- phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine washeated to 120 C. with concentrated hydrochloric acid for 6 hours to give8-chloro-2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a]-[1,4]benzodiazepin-l-one.

EXAMPLE 58-Chloro-2,4-dihydro-6-(2,6-difluorophenyl)-1l-l-striazolo-[4,3-a][1,4]benzodiazepin-1-oneIn the manner given in Example 1 1-bromo-8-chloro-6-(2,6-difluorophenyl)-4H-2-triazolo[4,3- a][1,4]benzodiazepine washeated with 85% phosphoric acid to give .8-chlor0-2,4-dihydro-6-(2,6-difluorophenyl)-lH-s-triazolo[4,3-a][1,4]- benzodiazepin-l-one.

EXAMPLE 68-Chloro-2,4-dihydro-6-(o-chlorophenyD-1H-striazolo[4,3-a][1,4]benzodiazepin-1-oneIn the manner given in Example. 1, 1-bromo-8-chloro-o-(o-chlorophenyl)-4l-l s-triazolo[4,3- ulllAlbcnzodiuzcpine isheated to 120 C. with 85% phosphoric acid for 6 hours to give8-chloro-2,4- dihydro-6-(o-chlorophenyl)-lH-s-triazolo-MJ-a][1,4]benzodia2epin-1-one.

EXAMPLE 78-Bromo-6(o-chlorophenyl)-2,4-dihydro-1I-l-striazolo[4,3-a][1,4]benzodiazepin-1-oneIn the manner given in Example 1,1,8-dibromo-6-(ochlorophenyl)-4H-s-triazolo[4,3- a][1,4]benzodiazepineis heated with 85% phosphoric acid to give8-bromo-6-(o-chlorophenyl)-1H-striazolo[4,3-a][ l,4]benzodiazepin-1-one= In the manner given in the preceeding exampleother 6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-

a][1,4]benzodiazepin-l-ones of formula II can be pro- PREPARATION 42,4-Dihydro8-chloro-2-methyl-6-(o-chlorophenyl]-1I-I-s-triazolo[4,3-a][1,4]benZodiazepin-l-one and its hydrochloride Asolution of 1.0 g. of 2,4-dihydro-6-(ochlorophenyl)-lI-I-s-triazolo[4,3-a][1,4]benzodiazepin-1-one in ml. of dry dimethylformamide in a nitrogenatmosphere is treated with 0.145 g. of sodium hydride (a 58% suspensionof Natl in mineral oil). This mixture is heated on the steam bath for 15minutes resulting in a solution. This solution is cooled in an ice bathand thereto is added 0.5 g. of methyl iodide in about 5 ml. of ether.After stirring the reaction mixture for 18 hours at about 2224 C., themixture is concentrated and the resulting residue chromatographed over100 g. of silica gel with an ethyl acetate-cyclohexane (in 1:1 by volumeratio) solution. The product is crystallized from ether-Skelly B to give2,4-dihydro-8-chloro-2-methyl-6-(o-chlorophenyl)-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-one having a melting point of82-84 C. The latter is converted with ethereal hydrogen chloride to itshydrochloride salt.

I claim:

11. A process for the production of a 2,4-dihydro-6-phenyl-lH-s-triazolo[4,3-a][1,4]benzodiazepin-1-one of the formula 11:

wherein the A-ring is substituted in position 8 with hydrogen, chlorineor bromine; and wherein the B-ring is substituted in the ortho positionswith hydrogen, chlorine, or fluorine, which comprises: Heating betweenl00-150 a compound of formula I l ll wherein X is chlorine or bromineand rings A and B are defined as above, with an aqueous mineral acid for1 to 10 hours, to obtain the compound of formula 11 above.

2. The process of claim 1 wherein the aqueous mineral acid is phosphoricacid.

3. The process of claim 11 wherein the starting compound I has theformula wherein X is bromine or chlorine.

41. The process'of claim 1 wherein the starting compound I has theformula wherein X is chlorine or bromine.

l l= =l= UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PatentNo. 5,856,809 Dated December 97 Inventor(8) Jackson B. Hester, JF-

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Face Page, Title "1H--S- should read lH-s- Column 1, title "lH-S-"should read lH-s- Column 2, line 42 "dost of" should read dose of Column2, line 44 "Ed should read E0 Column 2, line 56 "topic extensor" shouldread tonic extensor Column 6, Claim 1, Figure II ll should read T I N 20 SN 0 SN N Signed and Scalzd this Twenty-first ,Da 0 [SEAL] y MarchI978 RUTH C. MASON LUTRELLE F. PARKER Arresting Ojficer ActingCommissioner of Parents and Trademarks

1. A PROCESS FOR THE PRODUCTION OF A2,4-DIHYDRO-6-PHENYL1H-S-TRIAZOLO(4,3-A)(1,49BENZODIAZEPIN-1-ONE OF THEFORMULA II:
 2. The process of claim 1 wherein the aqueous mineral acidis 85% phosphoric acid.
 3. The process of claim 1 wherein the startingcompound I has the formula
 4. The process of claim 1 wherein thestarting compound I has the formula